ChemicalBook Product Catalog Biochemical Engineering Inhibitors protein tyrosine kinase Amuvatinib

Amuvatinib

Product NameAmuvatinib
CAS850879-09-3
MFC23H21N5O3S
MW447.51
EINECS
MOL File850879-09-3.mol

Chemical Properties

Density	1.443
storage temp.	Store at -20°C
solubility	≥22.4 mg/mL in DMSO; insoluble in H2O; insoluble in EtOH
form	solid
color	White to off-white
CAS DataBase Reference	850879-09-3

Usage And Synthesis

Description

Amuvatinib (also known as MP-470 or 850879-09-3), is a multi-targeted inhibitor of receptor tyrosine kinases that inhibits c-Kit, platelet-derived growth factor receptor α (PDGFRα), and c-Met (IC50s = 10, 40, and 81 nM, respectively). It inhibits growth and induces apoptosis in prostate cancer cell lines, with additive effects achieved when combined with erlotinib . Amuvatinib sensitizes cancer cells to radiation and chemotherapeutic compounds, in part by inhibiting homologous recombination.

Uses

MP-470 (Amuvatinib) is a potent and multi-targeted inhibitor of c-KitD816H, PDGFαV561D and Flt3D835Y with IC50 of 10 nM, 40 nM and 81 nM, respectively.

Definition

ChEBI: N-(1,3-benzodioxol-5-ylmethyl)-4-(4-benzofuro[3,2-d]pyrimidinyl)-1-piperazinecarbothioamide is a N-arylpiperazine.

Clinical Use

Amivantamab is the first drug approved by the FDA for the treatment of patients with NSCLC and EGFR exon 20 insertion mutations.

Synthesis

4-(piperazin-1-yl)benzofuro[3,2-d]pyrimidine

380339-27-5

Carbamothioic chloride, N-(1,3-benzodioxol-5-ylmethyl)-

1015482-56-0

850879-09-3

Example 21: 4-(Benzo[4,5]furo[3,2-d]pyrimidin-4-yl)piperazine-1-carbothioic acid (200 mg, 0.79 mmol) and pyridine (0.5 mL, 7.9 mmol) were dissolved in dichloromethane (20 mL), and N-(benzo[d][1,3]dioxol-5- ylmethyl)carbamoyl chloride was added slowly with stirring to a dichloromethane solution (20 mL). The reaction mixture was stirred overnight at room temperature. Upon completion of the reaction, methanol was added to quench the excess sulfur phosgene. The solvent was removed by concentration under reduced pressure and the residue was purified by silica gel column chromatography using 5% methanol/dichloromethane as eluent. The target fraction was collected and concentrated to give the crude product, which was further purified by recrystallization from dichloromethane/hexane to give a white solid product (150 mg, 37% yield). The structure of the product was confirmed by 1H NMR (CDCl3, 300 MHz) and FAB HRMS as expected. The results of elemental analysis were consistent with theoretical values.

target

c-KitD816H

Mode of action

Μechanisticly, amuvatinib inhibits tyrosine kinase receptor KIT through occupying its ATP binding domain (IC50 < 0.1 μM) and disrupts DNA repair through suppression of homologous recombination protein Rad51 as well as synergistic effects in combination with double stranded DNA damaging agents.

References

1. Effects of combining amuvatinib (MP-470) with DNA-damaging agents in osteosarcoma cell lines
2. Janssen submits supplemental biologics license application to the U.S. Food and Drug Administration seeking approval of RYBREVANT (amivantamab-vmjw) in combination with chemotherapy for the first-line treatment of patients with locally advanced or metastatic EGFR exon 20 insertion mutation-positive non-small cell lung cancer. News release.
3. Raoul Tibes, Gil Fine, Gavin Choy, Sanjeev Redkar, Pietro Taverna, Aram Oganesian, Amarpao Sahai, Mohammad Azab and Anthony W. Tolcher. A phase I, first-in-human dose-escalation study of amuvatinib, a multi-targeted tyrosine kinase inhibitor, in patients with advanced solid tumors. Cancer Chemother Pharmacol (2013) 71: 463-471
4. Gavin Choy, Rajashree Joshi-Hangal, Aram Oganesian, Gil Fine, Scott Rasmussen, Joanne Collier, James Kissling, Amarpal Sahai, Mohammad Azab and Sanjeev Redkar. Saftety, tolerability, and pharmacokinetics of amuvatinib from three phase 1 clinical studies in healthy volunteers. Cancer Chemother Pharmacol (2012) 70: 183-190